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& 2013 International Society of Nephrology
Acute kidney injury: global health alert
Philip Kam Tao Li1, Emmanuel A. Burdmann2 and Ravindra L. Mehta3, for the World Kidney Day Steering
Committee 20134
1
Department of Medicine and Therapeutics, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong;
Department of Medicine, University of Sao Paulo Medical School, Sao Paulo, Brazil and 3Department of Medicine,
University of California, San Diego, San Diego, California, USA
2
Acute kidney injury (AKI) is increasingly prevalent in
developing and developed countries and is associated with
severe morbidity and mortality. Most etiologies of AKI can be
prevented by interventions at the individual, community,
regional, and in-hospital levels. Effective measures must
include community-wide efforts to increase an awareness of
the devastating effects of AKI and provide guidance on
preventive strategies, as well as early recognition and
management. Efforts should be focused on minimizing
causes of AKI, increasing awareness of the importance of
serial measurements of serum creatinine in high-risk patients,
and documenting urine volume in acutely ill people to
achieve early diagnosis; there is as yet no definitive role for
alternative biomarkers. Protocols need to be developed to
systematically manage prerenal conditions and specific
infections. More accurate data about the true incidence and
clinical impact of AKI will help to raise the importance of the
disease in the community, increase awareness of AKI by
governments, the public, general and family physicians, and
other health-care professionals to help prevent the disease.
Prevention is the key to avoid the heavy burden of mortality
and morbidity associated with AKI.
Kidney International (2013) 83, 372–376; doi:10.1038/ki.2012.427;
published online 9 January 2013
KEYWORDS: acute kidney injury; World Kidney Day
Correspondence: Sara Martin, World Kidney Day Global Operations Center,
Rue du Luxembourg 22–24, Brussels 1000, Belgium.
E-mail: [email protected]
4
World Kidney Day (WKD) is a joint initiative of the International Society of
Nephrology and the International Federations of Kidney Foundations.
WKD Steering Committee members: Miguel Riella (Brazil, co-chair),
John Feehally (UK, co-chair), Timur Erk (Turkey), Paul Beerkens (The
Netherlands), Guillermo Garcia-Garcia (Mexico), Philip KT Li (Hong Kong),
William G. Couser (USA), Georgi Abraham (India), Luca Segantini
(Belgium), Sara Martin (Belgium)
Received 26 November 2012; accepted 29 November 2012; published
online 9 January 2013
372
On 14 March 2013, the 8th World Kidney Day (WKD) will be
celebrated. WKD is an annual event jointly organized by the
International Society of Nephrology and the International
Federation of Kidney Foundations. This year, we aim to alert
the public to the global increase in acute kidney injury (AKI)
in both developing and developed countries. AKI is a
syndrome of abrupt loss of kidney function, often with
oliguria, which is strongly associated with increased early and
long-term patient morbidity and mortality, as well as the
subsequent development of chronic kidney disease (CKD).
There is an urgent need for a global health strategy to
reduce the enormous growing burden of AKI and its
consequences. We advocate that efforts focused on preventing
AKI be coupled with early detection and treatment, and
adequate follow-up to reduce mortality and the long-term
burden of AKI-induced CKD.
EPIDEMIOLOGY OF AKI WORLDWIDE
The KDIGO (Kidney Disease Improving Global Outcome)
Clinical Practice Guideline for AKI defines AKI as any of the
following: increase in serum creatinine by X0.3 mg/dl
(X26.5 mmol/l) within 48 hours, increase in serum creatinine
to X1.5 times baseline, which is known or presumed to have
occurred within the prior 7 days, or urine volume o0.5 ml/
kg/h for 6 h.1 An epidemiological study in Scotland showed
that the incidence of AKI was 2147 per million population
per year (pmp),2 and in a community study in Northern
California the annual incidence of non-dialysis-requiring and
dialysis-requiring AKI were, respectively, 3841 and
244 p.m.p.;3 this incidence increased over time and was
consistently higher in men and in the elderly.3 Unfortunately,
there are still no comprehensive studies on the incidence of
AKI in the community in the developing world.
Recent hospital studies in the developed world report AKI
in 3.2–9.6% of admissions, with overall in-hospital mortality
around 20%, and up to 50% in ICU patients.4,5 There is also
increased long-term mortality in those with AKI surviving
hospitalization, with adjusted mortality risk of 1.4, which
augmented with increasing severity of AKI.5 AKI requiring
renal replacement therapy (RRT) occurs in 5–6% of ICU
patients, with an extremely high in-hospital mortality rate of
60%.6 It is estimated that about 2 million people die of AKI
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PKT Li et al. : Acute kidney injury
every year.6,7 Those who survive AKI have a higher risk for
later development of CKD.8
AKI IN THE DEVELOPING WORLD
Eighty-six per cent of the world’s population lives in low- and
middle-income countries, which have many contrasts and
inequalities. Sophisticated tertiary hospitals coexist with
inadequate primary care and poor health system infrastructure in the same country and even in the same city. In such
countries, AKI has a peculiar bimodal presentation. In
modern, large, urban centers, the pattern of AKI is very
similar to that found in the developed world; it is
predominantly a hospital-acquired disease occurring mostly
in older, critically ill multiorgan failure patients with
substantial comorbidity. The main cause for AKI in this
population is renal ischemia, principally due to sepsis, and is
often associated with nephrotoxic drugs.9
At the same time, in rural areas or smaller cities in the
countryside, AKI will usually be a community-acquired
disease, affecting younger and previously healthy individuals.
In this population, specific causes of AKI include diarrheal
diseases with dehydration, infectious diseases (malaria,
dengue, yellow-fever, leptospirosis, tetanus, and human
immunodeficiency virus), animal venoms (snakes, bees,
Loxosceles spiders, Lonomia caterpillars), septic abortion,
dyes, and natural medicines.10–12 Most of these factors
triggering AKI are associated with poverty and affect
vulnerable populations because of poor sanitation and
water hygiene (diarrheal diseases), a lack of education and
access to an adequate urban infrastructure, and difficulty in
having access to the health-care system (septic abortions,
snakebite, natural medicines, tetanus) and breaking of an
ecological balance from uncontrolled and unplanned
urbanization (leptospirosis, yellow-fever, Africanized bees,
and Lonomia caterpillar accidents).10–13 In the developing
world, the same ICU may have a typical bacterial
sepsis–induced AKI patient side by side with a patient
suffering from dengue or tetanus-induced AKI.
Increasingly, these causes of AKI may be exported from
developing to developed countries because of immigration,
business travel, tourism, and world warming.
AKI IN THE DEVELOPED WORLD
The availability of standardized criteria for diagnosis and
staging of AKI has made clear that the prevalence of AKI in
the developed world has increased in the past decade.14,15
AKI is now encountered in 45% of patients admitted to the
ICU and 20% of hospitalized patients.16,17 This increased
prevalence likely reflects an aging population burdened by
multiple comorbidities, which is often managed with
multiple drugs.18,19 AKI is a multifactorial entity.
Etiological factors include prerenal injury contributing to
reduced renal perfusion; however, the precipitating events are
often iatrogenic, e.g., hypotension during anesthesia and
surgery, or profound diarrhea secondary to C. difficile
infection resulting from aggressive antibiotic therapy.20
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Drug-induced kidney injury is recognized as a major factor
in about 20% of cases, whereas hospital-acquired infections,
sepsis, complex surgery, and diagnostic procedures requiring
intravenous contrast continue to be significant risk factors for
the development of AKI.21–23 Patients in the ICU are dying of
AKI and not just simply with AKI. Experimental and small
observational studies have shown that AKI negatively affects
immunity and is associated with higher rates of infection.24
AKI patients frequently develop a vicious cycle of immune
dysfunction, sepsis, and multiorgan failure. Indeed, severe
sepsis is currently the major cause of AKI in the United
States.25 The host response to sepsis involves an
inflammatory response that activates innate immunity. If
this persists, the immune response will lead to a release of a
multitude of proinflammatory products, which frequently
cause organ dysfunction, including kidney failure.26
A key issue in the developed world is that patients are
increasingly cared for by multiple providers, often in different
health-care systems, with infrequent or minimal data sharing
between providers and across health-care systems. This lack
of knowledge often results in overdosing of nephrotoxic
medications, for example, a dentist might prescribe large
doses of nonsteroidal anti-inflammatory drugs for pain
management after dental surgery without the knowledge of a
patient’s underlying CKD, thus contributing to development
of AKI superimposed on the CKD. As kidney disease is
generally silent, unless it is severe enough to reduce urine
output or lead to complications, it can often go unrecognized.27 A recent national audit of the care provided to
patients who died with a diagnosis of AKI in United
Kingdom hospitals revealed several shortcomings. AKI was
often diagnosed late in the course, the initial severity was
underestimated, and diagnostic and therapeutic interventions
were often incomplete or delayed.28 This audit illustrates the
urgent need for improving awareness of AKI and has
prompted the medical community in the UK to implement
specific measures to facilitate early recognition, timely
diagnosis, and appropriate management and follow-up of
AKI patients.29
AKI IN CHILDREN
The epidemiology of pediatric AKI has shifted in the past
decades from intrinsic kidney diseases such as hemolytic
uremic syndrome and glomerulonephritis to ischemia,
nephrotoxins, and sepsis in critically ill children.17
Estimates of the incidence of AKI in children vary
depending on the definition used and the population
assessed, but it is clearly increasing. A pediatric-modified
RIFLE (risk, injury, failure, loss, and end-stage kidney)
criterion was developed and validated in 2007. The major
difference with the original RIFLE definition is the use of
changes in estimated creatinine clearance calculated by
Schwartz formula rather than serum creatinine, in view of
the large variation in body mass in children.17 Development
of AKI has been consistently demonstrated as an independent
risk factor for death in children, from neonates to
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adolescents. Recently, the concept of ‘renal angina’ was
proposed as a tool to the early identification of kidney injury
together with early adoption of preventive measures in
children at high risk for the development of AKI.30 One of
the strongest indicators of ‘renal angina’ and risk of further
development of AKI in children is fluid overload.17,30 As in
adults, AKI carries a significant risk for late development of
CKD in surviving children.17,31
OTHER CONSEQUENCES OF AKI
Apart from the high mortality associated with AKI, there are
other major consequences. Patients with AKI utilize more
resources and have longer hospital lengths of stay partly
because of the effect of AKI on other organ functions. For
instance, AKI patients have more difficulty being weaned off
ventilators.32 AKI patients are more prone to fluid overload,
with a resultant increase in mortality and impaired renal
recovery.33 When patients leave the hospital, they generally
require prolonged recuperation often in skilled nursing
facilities and may not recover kidney function.34 In a study
of over 4000 type 2 diabetic patients in the Veterans Affairs
health-care system in the USA, approximately half required
one or more hospitalizations, and among those requiring
hospitalization 29% experienced at least one episode of
AKI.35 CKD is now recognized as a major noncommunicable
disease, and data in the same study of type 2 diabetics showed
that AKI was an important independent risk factor for stage 4
CKD (hazard ratio 3.56), with each AKI episode doubling
that risk. There is other consistent and increasing evidence
that AKI contributes to CKD development and may result in
dialysis dependency.8,36 Collectively, these data demonstrate
the high personal and community costs of an episode of AKI
and stress the pressing need to address this problem in an
effective way.37
IS AKI PREVENTABLE AND TREATABLE?
A central tenet of the WKD message since 2006 has been that
‘kidney disease is common, harmful, and treatable’. Similar to
CKD, AKI is common, harmful, and treatable, and is also
largely preventable.
The heterogeneity of patients and the broad range of
situations where AKI is encountered make it challenging to
standardize an approach for evaluating and managing
patients with this syndrome. The recent KDIGO guidelines
for management of AKI provide a useful reference to assist
clinicians for managing AKI; however, the successful
implementation of guidelines and their application to
individual patients can be slow and requires concerted
efforts.1,38
Prevention of AKI starts in the community with prompt
assessment of those at risk, for example, in taking prompt
action following effective evaluation of the severity of fluid
depletion in acute diarrhea. Regular drug therapy can
compound that risk, and the many older people taking
nonsteroidal anti-inflammatory drugs or renin–angiotensin
system blockers should be educated to discontinue them
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PKT Li et al. : Acute kidney injury
temporarily in the face of acute intercurrent illness, a socalled ‘medication holiday’.
In the developed world, the growing adoption of
electronic medical records provides several opportunities
for managing patients through the continuum of outpatient
and in-hospital care. Several studies have now shown that
active surveillance for changes in creatinine can automate
alerts to guide drug dosing and reduce the incidence of druginduced kidney injury.39,40 An ‘AKI sniffer system’ embedded
in the electronic medical record to warn physicians of
changing renal function has been shown to increase the
number and timeliness of early therapeutic interventions.41
The emerging field of kidney-specific biomarkers of damage
will additionally offer opportunities to improve care.42
Several studies have now shown the ability of various
biomarkers alone or in combination to facilitate earlier
diagnosis and improve differential diagnosis of AKI.
However, biomarker-guided interventions have not as yet
been shown to be of benefit,43 and currently serum creatinine
and urinary volume remain the clinical pointers to AKI
diagnosis. Given advances in medical informatics, biomarker
development
and
interpretation,
and
therapeutic
interventions, it is now imperative that we leverage these
advances to educate physicians and care providers about AKI
and provide them with the tools to manage these patients
timely and effectively.
In the hospital setting, AKI preventive measures continue
to be adequate hemodynamic control, hydration, hematocrit
and oxygen profiling, and avoidance of nephrotoxic drugs;
other preventive maneuvers should be implemented for
particular diseases or conditions causing AKI. In the
developing world, awareness of the specific infectious or
venomous organisms in certain areas will allow environmental protection, vaccines, pharmacological prophylaxis,
and early administration of anti-venom. Early and adequate
anti-venom administration is a valuable preventive maneuver
for snakebite and caterpillar venom–induced AKI, reducing
its morbidity and lethality.10,13 Prompt diagnosis, timely
hemodialysis, and adequate supportive therapy are associated
with improved outcome in tropical infectious disease–
associated AKI, such as leptospirosis and malaria.10,44,45 As
always, the early diagnosis of AKI is the key to minimize
further insults.
Prevention for AKI is clearly the key to avoid the heavy
burden of mortality and morbidity associated with this
syndrome (Table 1), and this will only come about through
increasing awareness of the true incidence and clinical impact
of AKI among governments, the public, general and family
physicians, and other health-care professionals. Most etiologies of AKI can be prevented by interventions at the
individual, community, regional, and in-hospital levels.
Effective measures must include community-wide efforts to
increase an awareness of the devastating effects of this illness
and provide guidance on preventive strategies and for early
recognition and management. Efforts should be focused
on minimizing AKI causes, increasing awareness of the
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PKT Li et al. : Acute kidney injury
Table 1 | Strategies for preventing AKI
Government
Funding support for acute kidney injury (AKI) research in hospital and
community on AKI incidence, outcome, and mortality
Funding support for setting up AKI registries
Recognition of natural hazards for AKI: water sanitation, flooding,
venomous animals
Recognition of AKI in common infections: malaria, dengue, leptospirosis,
HIV, postinfectious hemolytic uremic syndrome
Better obstetric care
Collaboration with health-care professionals on educating the public
about AKI prevention
protecting the kidneys from this lethal syndrome is an
important health strategy for the patient and the community.
The effective implementation of such strategies will only
come when both the general public and the renal community
work together to convince health authorities of the pressing
need to do this. Government and health authorities must
allocate resources to manage this problem both in the
developed and developing world.
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Public
Awareness of the potential problems of AKI and avoid unsupervised,
indiscriminate, and long-term use of nephrotoxic drugs and natural
substances
General practitioners and physicians
Awareness of patients at risk for AKI and situations contributing to AKI
Awareness of prerenal causes of AKI and of the need for early and
appropriate rehydration and hemodynamic optimization in hypovolemic
patients
Awareness of natural and man-made nephrotoxin, nephrotoxic drugs,
herbs, and indigenous medicine
Judicious use of nephrotoxic drugs and awareness of potential drug
interactions
Early recognition of AKI and early referral to nephrologists
Nephrologists
Establish and implement common AKI diagnostic criteria and definitions
for prevention, treatment, and research
Find new diagnostic tools including inexpensive technology and
biomarkers for AKI diagnosis and monitoring
Adapt renal replacement therapy to regional needs, technique, and
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Peritoneal dialysis (PD) should also be considered for AKI,
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The worldwide celebration of WKD 2013 provides an
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